Endothelial cells and endothelial progenitor cells in the pathogenesis of systemic sclerosis

Abstract

Systemic sclerosis (SSc) is a connective tissue disease characterized by excessive fibrosis, microvasculopathy, and autoimmunity. Endothelial cell (EC) injury and subsequent endothelial cell dysfunction is believed to be an initial event that eventually leads to a vicious pathogenic cycle. This process is further enhanced by defective angiogenesis and vasculogenesis, as the vascular repair machinery does not work properly. Endothelial progenitor cells (EPCs) are functionally and quantitatively insufficient to recover the endothelium in SSc patients. The dysfunctional ECs and EPCs not only trigger the formation of typical vascular lesions, such as progressive intimal fibrosis in small arteries and the loss of capillaries, but also promote a series of inflammatory and profibrotic processes, such as endothelial-mesenchymal transition and recruitment and accumulation of monocytic EPCs with profibrotic properties. These processes together contribute to the accumulation of extracellular matrix in the affected tissue. This review features current insights into the roles of ECs and EPCs in the pathogenesis of SSc.

Figure 1

Roles of ECs and EPCs in pathogenesis of SSc. A variety of triggers damage the endothelium, leading to subsequent expression of a series of pro-angiogenic factors, growth factors, and chemokines. Increased levels of these mediators promote recruitment of conventional EPCs from bone marrow, however, the vascular repair machinery is intrinsically impaired, which results in altered EC functions that induce the activation of fibroblasts by a direct interaction and their trans-differentiation into myofibroblasts via Endo-MT. Additionally, in compensation for the insufficient vascular repair process, monocytic EPCs with M2 features are recruited into circulation and are made to accumulate at the affected sites, thereby promoting ECM deposition and tissue fibrosis. ECs: endothelial cells; vSMCs: vascular smooth muscle cells; EPCs: endothelial progenitor cells; VEGF: vascular endothelial growth factor; FGF-2: basic fibroblast growth factor-2; MCP-1: monocyte chemoattractant protein-1; SDF-1: stromal-derived factor-1; MMP12: matrix metalloproteinase 12; TGF-β: transforming growth factor β; ECM: extracellular matrix.